Tracers labeled with short-lived positron emitting radionuclides (e.g. 11C, t1/2=20.3 min) are frequently used in various non-invasive in vivo studies in combination with positron emission tomography (PET). Because of the radioactivity, the short half-lives and the submicromolar amounts of the labeled substances, extraordinary synthetic procedures are required for the production of these tracers. An important part of the elaboration of these procedures is development and handling of new 11C-labelled precursors. This is important not only for labeling new types of compounds, but also for increasing the possibility of labeling a given compound in different positions.
In 11C-labelling synthesis [11C]carbon dioxide is the most versatile of the primary precursors (radionuclide labeled compound obtained in a target) with respect to production yield, ease of separation from target gas and prospect for chemical transformation. [11C]Carbon dioxide, is readily obtained from the N(p,α)11C reaction by presence of low concentrations of oxygen. It is particularly useful in reactions with organo lithium compounds and Grignard reagents which give access to important tracers such as acetate and palmitate labeled in the carboxylic position. Carboxylation reactions using [11C]carbon dioxide has a primary value for PET-tracer synthesis since biologically active substances often contain a carboxyl group or functionalities that can be derived from a carboxyl group.
The reaction of [11C]carbon dioxide with a Grignard reagent followed by reduction with lithium aluminum hydride (LAH) and finally iodination with hydroiodic acid is a versatile method for synthesis of 11C-labelled organo iodides. The 11C-labelled organo iodides are valuable precursors that can be used for the labeling of a broad range of biological active compounds. There are, however, several problems associated with this method. The Grignard reagents usually contains the corresponding non radioactive compound, from reaction with atmospheric carbon dioxide, which leads to isotopic dilution and decrease of the specific radioactivity. In order to minimize the isotopic dilution and facilitate automation, the use miniaturization and reagent coated reaction loops are valuable approaches. In the case of higher boiling organo iodides such as benzyl iodide the recovery from the hydroiodic acid has to be performed using extraction; an operation that is relative difficult to automate. Miniaturization and the use of reaction loop techniques is one way to circumvent the problems.
When prior art was applied in the synthesis of [11C]benzyl iodide using phenyl magnesium bromide coated on a reaction loop, the elution of the [11C]benzoate from the loop using diethyl ether failed. The reason was that the Grignard reagent precipitated during the transfer of the [11C]carbon dioxide and encapsulated the [11C]benzoate. The use of diethyl ether was a necessary requirement for the succeeding LAH-reduction and hydro iodination reaction.
In a similar investigation [11C] acetate was synthesized using a reaction loop coated with methyl magnesium bromide and [11C]carbon dioxide handled with prior art. The results suffered from bad reproducibility, low trapping efficiency of [11C]carbon dioxide and high levels of the side products [11C]acetone and [11C]tert-butanol.
In most previous methods the relative large volume of gas used for carrying the [11C]carbon dioxide has been allowed to flow through the reaction compartment and the [11C]carbon dioxide has been trapped solely by the process of conversion to products. There are several drawbacks and limitations with this method.                The trapping efficiency is determined by the amount and concentration of the reagent (e.g. Grignard reagent). This limit the possibilities for miniaturization and simplification (e.g. omit purification). A high concentration of the reagent may also lead to increased side reactions (e.g. in the synthesis of [1-11C]acetate further addition of methyl magnesium bromide will give [11C]acetone and [11C]tert-butanol as side products).        The flow of carrier gas through the reaction compartment will, in the case volatile solvents are used, lead to evaporation of solvent, which will lead to an increased concentration and possible precipitation of the reagent. This may lead to increased side reactions and difficulties in subsequent eluting the radioactive product from the compartment.        Due to the relative large volume of carrier gas and the need of using a relative low flow during the transfer of [11C]carbon dioxide in order to obtain high trapping efficiency, the time span of the transfer is long. This may lead to a distribution in reaction time for the batch of [11C]carbon dioxide with several 100%.        If weakly reactive reagents are used, that requires several minutes for conversion of the [11C]carbon dioxide, the fraction of the radioactivity that will be trapped by passage through the reagent will be low.        
When compounds are labeled with 11C, it is usually important to maximize specific radioactivity. In order to achieve this, the isotopic dilution and the synthesis time must be minimized. Isotopic dilution from atmospheric carbon dioxide may be substantial when [11C]carbon dioxide is used in a labeling reaction and is usually proportional to the amount of reagent. Miniaturization of synthesis equipment and minimization of the amounts of reagents is an important approach for increase of specific radioactivity in this context.
The cold-trap technique is widely used in the handling of 11C-labelled precursors, particularly in the case of [11C]carbon dioxide. The procedure has, however, only been performed in one single step and the labeled compound was always released in a continuous gas-stream simultaneous with the heating of the cold-trap. Thus, the option of using this technique for radical concentration of the labeled compound and miniaturization of synthesis systems has not been explored. This is especially noteworthy in view of the fact that the amount of a 11C-labelled compound usually is in the range 20-60 nmol.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.